Psychiatry and Clinical Neurosciences 2015; 69: 649–657
doi:10.1111/pcn.12308
Regular Article
Therapeutic effect of Avonex, Rebif and Betaferon on quality of life in multiple sclerosis Naghmeh Mokhber, MD,1† Amir Azarpazhooh, PhD,3,4,5† Elias Orouji, MD,2 Bita Khorram, MD,2 Morteza Modares Gharavi, PhD,1 Sorayya Kakhi, MD,2 Hoda Khallaghi, MD2 and Mahmoud Reza Azarpazhooh, MD2* 1 Psychiatry and Behavioral Sciences Research Center, 2Department of Neurology, Ghaem Medical Center, Mashhad University of Medical Sciences, Mashhad, Iran, and 3Department of Biological and Diagnostic Sciences, Faculty of Dentistry, 4Institute of Health Policy, Management and Evaluation, Faculty of Medicine, and 5Toronto Health Economics and Technology Assessment Collaborative, University of Toronto, Toronto, Canada
Aims: The aim of this study was to evaluate the effect of various disease-modifying therapies (DMT) on quality of life in multiple sclerosis (MS). Methods: This was a three-arm parallel study with balanced randomization in which 90 newly diagnosed, definite MS subjects referred to Ghaem Medical Center, Mashhad, Iran were enrolled between 2006 and 2009. Patients were randomly allocated into three DMT groups: Avonex, Rebif and Betaferon. Health-related quality of life was assessed in MS patients at baseline and 12 months after treatment with DMT using the MS Quality of Life-54 questionnaire. Results: Both mental and physical health scores improved within all three treatment groups after 12 months of treatment; however, this increase was only
ULTIPLE SCLEROSIS (MS) is the most common demyelinating disorder of the central nervous system that usually affects young adults.1 The disease is characterized by multifocal, inflammatory, and immune-mediated central nervous system injury,
M
*Correspondence: Mahmoud Reza Azarpazhooh, MD, Department of Neurology, Ghaem Medical Center, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran. Email: [email protected] † These authors contributed equally to the article. Clinical trial registration code: IRCT201404195280N16 (http:// www.irct.ir) Received 17 October 2014; revised 11 March 2015; accepted 18 April 2015.
significant in the mental health composite in the Betaferon group (P = 0.024). Betaferon had the highest mental health score change (14.04) while this change was 7.26 for Avonex (P = 0.031) and 5.08 for Rebif (P = 0.017). A physical health composite score comparison among the three treatment groups revealed no significant results.
Conclusions: With a positive impact of DMT on mental and physical dimensions of QOL in MS patients, initiation of treatment soon after diagnosis is recommended. In MS patients with more mental issues and fewer physical disabilities, Betaferon might be considered as a better choice of treatment. Key words: disease-modifying therapies, multiple sclerosis, quality of life.
which can cause a variety of symptoms and consequently requires comprehensive medical care.2–4 MS, as a long-term illness, can result not only in physical disabilities, but also in substantial mental health problems influencing the quality of life (QOL) of patients, their partners, families, and caregivers.5–7 The health-related QOL, or the capacity to derive satisfaction from meaningful behavior despite disease, is a topic of increasing interest to clinicians caring for MS patients. Hence in patients with MS, apart from complete psychophysical and objective neurologic status, a subjective perception of signs and symptoms, known as QOL, needs to be considered.8 Several studies have clearly shown that MS patients
© 2015 The Authors Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
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have lower QOL scores than healthy controls.5,9 In recent years, there has been an increasing tendency to evaluate the QOL in MS patients as the primary clinical outcome.10,11 Disease-modifying therapies (DMT) have a beneficial effect on the course of MS in terms of reducing the relapse rates and delaying the onset and progression of disabilities.12–17 In spite of limited data on QOL and its correlation with DMT, it is possible that DMT influence the QOL, independent of the physical disabilities.18 As treatment with β-interferon (IFN-β) is a life-long treatment and patients often experience various side-effects, a positive effect on the patient’s QOL is critical.12–14,19 Therefore, this study investigates the effect of DMT (IFN-β-1a [Avonex and Rebif] and IFN-β-1b [Betaferon]) on QOL in a group of MS patients.
distinct commercially available forms of IFN-β: Avonex, Rebif, and Betaferon. Avonex was administered 30 μg once per week via intramuscular injection. Rebif was administered 44 μg three times per week via subcutaneous injection. Betaferon was administered 0.25 mg every other day via subcutaneous injection. Patients (or their caregivers) were trained by the study neurologist (M.R.A.) to self-administer their assigned medication.
METHODS Study design The current study was a single blind, three-arm clinical trial, with balanced randomization to evaluate the effect of IFN-β on QOL of the patients with definite MS. The study was approved by the Ethics Committee of the Mashhad University of Medical Sciences (protocol no. 84394). Written informed consent was obtained from each participant prior to the investigations.
Study population The study began in May 2006, when we began gathering new MS patients, and lasted until June 2009. All new cases of definite MS referred to the Department of Neurology at Ghaem Medical Center, Mashhad, Iran were included in this study. MS was defined according to the revised McDonald criteria, which evaluate frequency of clinical attacks, number of objective lesions and specify additional requirements to make a diagnosis in each case.20 Patients were excluded if they had a history of substance abuse, treatment with any other type of DMT or had any signs of depression using semi-structural psychiatric interviews as well as the Beck Depression Inventory (Fig. 1).
Treatment protocol Patients were randomly assigned using a computergenerated list of random numbers to receive three
Neuropsychological outcome measures The following outcomes were measured at baseline and after 12 months of treatment: 1 QOL was assessed using the Farsi version of the MS Quality of Life (MSQOL)-54 scale,6 which has been previously validated.21 This scale is composed of the Short Form 36-item Health Survey and 18 disease-specific items. This 54-item self-reported questionnaire measures both mental and physical health. The Mental Health (MH) composite consists of five subscales: Health distress, Overall QOL, Emotional well-being, Role limitations due to emotional problems, and Cognitive function. The Physical Health (PH) composite consists of eight subscales: Physical function, Health perceptions, Energy/fatigue, Role limitations due to physical problems, Pain, Sexual function, Social function, and Health distress. MH and PH composite scores could have the value of 0–100 with higher values indicating better QOL. The Health distress scale is the only scale that does not individually load on mental and physical health but has high loadings on both. The internal consistency reliability of the MSQOL-54 test is 0.75–0.96 and the test–retest intraclass correlation coefficient is 0.66–0.96.6 2 The Expanded Disability Status Scale (EDSS) was also performed for all cases to quantify disability in eight Functional Systems. EDSS steps 1.0–4.5 refer to people with MS who are fully ambulatory. EDSS steps 5.0–9.5 are defined by the impairment to ambulation.22
Statistical analyses To investigate the effect of the treatment protocols on QOL, we calculated several sample sizes for each of the MH and PH composites and treatment groups. Then the largest calculated sample size was selected
© 2015 The Authors Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
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Quality of life in multiple sclerosis 651
Relapsing remitting MS patients assessed for eligibility (n = 90)
Excluded patients (n = 21) Previous treatment with any type of DMT (n = 14) History of substance abuse (n = 3) Signs of depression (n = 4)
Relapsing remitting MS patients who underwent randomization (n = 69)
Allocated for the treatment with Avonex (n = 23)
Allocated for the treatment with Rebif (n = 23)
Allocated for the treatment with Betaferon (n = 23)
Withdrawn/loss to follow up (n = 3) • Refusal (n = 1) • Loss of contact (n = 2) Analyzed for QOL (n = 20)
Withdrawn/loss to follow up (n = 2) • Refusal (n = 2)
Withdrawn/loss to follow up (n = 4) • Refusal (n = 1) • Loss of contact (n = 3) Analyzed for QOL (n = 19)
Analyzed for QOL (n = 21)
Figure 1. Flow diagram of the randomized controlled study. DMT, disease-modifying therapies; MS, multiple sclerosis; QOL, quality of life.
for the study. The minimum sample size of 18 patients per group was calculated using two independent means t-tests. To calculate MH composite score, the final score of each of the five subscales was multiplied by weight for this subscale (respectively, 0.14, 0.18, 0.29, 0.24, and 0.15). These five subtotal values were then added to generate the MH composite score. The same approach was undertaken for the PH composite score, except there were eight subscales, respectively weighted by 0.17, 0.17, 0.12, 0.12, 0.11, 0.08, 0.12, and 0.11.6,19 The percentage of missing data concerning the MSQOL-54 questionnaire was very low, therefore no imputation was performed for the missing data.
Results were compared among and within the three treatment groups to evaluate the impact of intervention medications on patients’ QOL during this 1-year period. Statistical analyses were performed using SPSS 18 (SPSS, Chicago, IL, USA). The Lilliefors (Kolmogorov–Smirnov) test was applied to assure the normal distribution of the data. Parametrical tests, such as paired samples t-tests and analysis of variance with post-hoc analysis using Tukey’s Honestly Significant Difference, were used to assess the statistical significance of the continuous variables, within and among groups, respectively. A value of P ≤ 0.05 was used as a criterion for statistical significance.
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(Table S1). There was no significant difference in age, sex, or education level of participants among the three groups.
RESULTS Demographic data Overall, 90 MS patients participated in this study. A total of 21 patients were excluded due to previous history of using DMT, history of substance abuse, and having signs of depression. The 69 remaining patients were allocated to the three treatment groups (23 patients in each group) and were followed up for a minimum of 12 months. We lost three patients in the Avonex group (one refused to continue, two loss of contact), two patients in the Rebif group (both did not continue the study due to changing their place of residence), and four patients in the Betaferon group (three loss of contact, one refused to continue), leaving us with 60 patients who completed the study (Fig. 1). The mean age of patients was 29.80 ± 7.51 years. There were 21 (35.0%) men and 39 (65.0%) women in the sample
(a)
Health-related QOL In all three treatment groups, Overall QOL scores were increased (Avonex: 58.83 to 65.96; Rebif: 57.46 to 64.27; and Betaferon: 59.42 to 69.15). Scores for both PH and MH composites were increased after 1 year in the whole group of MS patients (PH: 57.69 to 64.44; MH: 59.44 to 68.48). No significant difference was observed in the baseline summary scores of the MSQOL-54, MH and PH among the three groups (P = 0.311). There was a trend towards improvement in the MH and PH scores within each group of treatment after 12 months; however, only the MH composite score in Betaferon-treated patients showed a statistically significant improvement (58.89 to 72.93, P = 0.024) (Fig. 2a).
Summary score (within the groups) *
100
Mean score
80 60 40 20 0 PH
MH
PH
Avonex
MH
PH
Rebif
MH Betaferon
(b)
Score change (Δ) *
Summary score change 20 18 16 14 12 10 8 6 4 2 0 PH
(P = 0.031)* (P = 0.017) *
MH
Figure 2. (a) Comparison of summary score at ( ) baseline and ( ) after 12 months within each treatment group for the physical health (PH) and mental health (MH) components. (b) Comparison of summary score change between the ( ) Avonex, ( ) Rebif and ( ) Betaferon groups for the PH and MH components.
© 2015 The Authors Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
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Table 1. MSQOL-54 and EDSS values at baseline and after 12 months of treatment in the different treatment groups
Baseline
12 months
Pvalue
Baseline
12 months
Pvalue
Baseline
12 months
Palue
P-value (changes in three groups)
56.82 ± 22.99 44.82 ± 28.59 55.12 ± 13.35 45.25 ± 17.17 61.83 ± 25.92
63.83 ± 23.29 48.35 ± 18.29 75.94 ± 11.65 34.83 ± 20.08 72.08 ± 28.67
NS NS 0.046 NS NS
56.31 ± 19.12 40.71 ± 17.59 52.53 ± 16.12 47.50 ± 16.67 39.92 ± 17.58
64.14 ± 25.84 48.41 ± 20.29 65.41 ± 18.18 67.67 ± 15.58 42.42 ± 23.92
NS NS NS 0.036 NS
59.96 ± 27.45 41.82 ± 27.76 66.18 ± 18.00 66.75 ± 25.25 40.00 ± 18.33
65.37 ± 28.65 49.76 ± 31.18 62.00 ± 23.65 78.58 ± 23.00 43.50 ± 19.75
NS NS NS NS NS
NS NS 0.009 0.031 0.043
76.09 ± 29.00 53.00 ± 28.50 60.25 ± 26.17 64.91 ± 18.91 60.84 ± 18.13 64.93 ± 20.79 59.00 ± 10.83 64.45 ± 19.48 46.71 ± 18.08
87.64 ± 38.64 58.25 ± 32.35 65.83 ± 27.17 69.73 ± 20.55 68.1 ± 20.72 69.71 ± 14.57 65.44 ± 14.11 63.72 ± 21.17 59.33 ± 22.04
NS NS NS NS NS NS NS NS NS
86.45 ± 22.55 72.88 ± 28.13 65.50 ± 19.83 61.55 ± 19.73 58.61 ± 19.82 61.50 ± 20.29 50.61 ± 11.39 58.86 ± 18.28 49.67 ± 17.75
84.73 ± 35.18 69.38 ± 39.25 67.17 ± 29.50 78.64 ± 36.45 64.41 ± 23.65 78.64 ± 28.79 64.06 ± 18.94 66.52 ± 23.10 43.29 ± 21.42
NS NS NS NS NS NS NS NS NS
91.27 ± 59.45 62.63 ± 23.38 54.92 ± 24.50 65.00 ± 28.09 58.89 ± 24.31 67.14 ± 29.64 39.17 ± 19.72 68.55 ± 23.24 53.00 ± 23.04
86.91 ± 50.36 69.13 ± 30.38 64.25 ± 27.83 81.09 ± 26.27 72.93 ± 28.12 81.79 ± 28.07 75.33 ± 37.28 78.31 ± 24.48 60.17 ± 20.79
NS NS NS NS 0.024 NS 0.021 NS NS
0.038 NS NS NS 0.017 NS 0.021 0.034 0.019
74.87 ± 20.27 1.5 ± 1.0
92.27 ± 31.40 1.5 ± 0.6
NS 0.548
79.33 ± 35.80 2.3 ± 1.5
81.27 ± 29.13 1.3 ± 0.9
NS 0.001
65.60 ± 28.93 2.1 ± 1.0
71.80 ± 35.93 1.5 ± 1.0
NS 0.028
0.026 0.003
Avonex
MSQOL-54 MSQL-PH Physical function Health perceptions Energy/fatigue Role limitations – physical Pain Sexual function Social function Health distress MSQOL-MH Health distress Overall quality of life Emotional well-being Role limitations – emotional Cognitive function EDSS
Rebif
Betaferon
Bold font indicates summary scores and significant P-values. EDSS, Expanded Disability Status Scale; MH, mental health; MSQOL, Multiple Sclerosis Quality of Life scale; NS, not significant; PH, physical health.
Within each group, there were specific subscales that changed significantly after 12 months. These included the Health perception subscale in the Avonex group (change = 20.82, P = 0.046), the Energy/fatigue subscale in the Rebif group (change = 20.17, P = 0.036) and the Overall QOL as a subscale of MH in the Betaferon group (change = 36.17, P = 0.021). Among the study groups, Avonex had the best effects on MS patients in terms of the Health perception (P = 0.009), Role limitations – physical (P = 0.043), Pain (P = 0.038), Role limitation – emotional (P = 0.019) and Cognitive function subscales (P = 0.026). Rebif had the best effects on the Energy/fatigue subscale (P = 0.031). Betaferon improved the Overall QOL (P = 0.21) and Emotional well-being (P = 0.034) subscales better than the other two treatments (Table 1, Fig. 3). Figure 2b presents the inter-group comparisons. No significant difference in PH composite score was found among the three groups. Yet a significant change on the MH composite score was noted in the Betaferon group (14.04) as compared to the Avonex (7.26, P = 0.031) and Rebif (5.08, P = 0.017) groups.
Disability There was no difference in the EDSS baseline values among the three treatment groups (P = 0.37). The
baseline range of EDSS was 0–5.5 and this range was 0–4.0 after 12 months of treatment. Within each group, participants who received Rebif (P = 0.001) and Betaferon (P = 0.028) experienced an improvement in their disability; however, those who received Avonex did not (P = 0.548). Inter-group comparison between the three groups indicated Rebif to have the best effect on the improvement of disability in MS, and Avonex to have the least impact (P = 0.003) (Table 1).
DISCUSSION QOL is an important aspect of health in patients with MS. Previous studies have shown that QOL measurements are constantly lower in patients with MS.9,23–25 The assessment of QOL is being increasingly recognized as a method to analyze the efficacy of different treatment modalities.5,7–9,18,26–30 In particular, it has been shown that DMT can improve some aspects of patients’ QOL.18,26–30 To date, there is no study addressing the comparison between different treatment options. Hence, we designed this single blind clinical trial to investigate the effect of IFN-β-1a (Avonex and Rebif) and IFN-β-1b (Betaferon) on QOL in a group of patients with definite MS. Due to the unavailability of glatiramer acetate (Copaxone) on a large scale in Iran, we were not able to include it
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MSQOL-54 subscale score change
10
*
8
Score change (Δ)
6 *
* 4 *
* *
* *
2
0
Physical healt h
Cognitive function
Role limitations – emotional
Emotional well-being
Overall quality of life
Health distress
Health distress
Social function
Sexual function
Pain
Role limitations - physical
Energy/fatigue
Health perceptions
−4
Physical function
−2
M ent al healt h
Figure 3. Comparison of subscale score change between the ( ) Avonex, ( ) Rebif and ( ) Betaferon groups. MSQOL-54, Multiple Sclerosis Quality of Life-54 scale.
in our study. Furthermore, due to the need for administration of comprehensive tests to assess sideeffects of these treatments, including depression, which is believed to be worsened, these side-effects were not investigated here. We used the MSQOL-54 as a self-administered, multidimensional healthrelated QOL measure, which combines both generic and MS-specific items into a single instrument. It is the most frequently used specifically MS questionnaire. This questionnaire has a high test–retest reliability and internal consistency with evidence supporting its content and construct validity.6 Our study population constituted newly diagnosed MS patients who had not taken any previous treatment for MS. Such homogeneity eliminates the bias
of the late effects of other previous treatments on measuring QOL; however, we were limited with respect to the number of patients in each group. Our results showed a significant improvement in the MH composite of the MSQOL-54 after 12 months of treatment with Betaferon compared to the Avonex and Rebif groups. Moreover, all of the subscales of MH in the Betaferon group showed an improving trend, while for the other two groups, we noticed decreasing values in at least one of the subscales. However, it should be noted that each individual subscale might or might not be in line with the composite improvement. Unlike mental health, physical health showed the lowest improvement in the Betaferon group com-
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Quality of life in multiple sclerosis 655
pared to the Avonex and Rebif groups and the best improvement was seen in the Avonex group. In general, no obvious difference was observed in terms of the PH or MH composites in the Avonex and Rebif groups. However, the impact of these two treatments was different to that of Betaferon, which acts relatively better in MH scales. IFN-β could prevent MS attacks, improve the physical status of the patients and consequently lead to the improvement of QOL. It is also possible that these treatments can change the course of the disease by improving cognitive status and hence, directly affecting the patients’ QOL.31 Furthermore, the impact of IFN on the immune system may also lead to overall well-being in patients. In a large group of untreated MS patients, Putzki et al.32 found that treatment initiation with intramuscular IFN-β-1a attenuates MS disease activity and improves QOL. Similarly, in a 2-year follow-up study, Jongen et al.33 found that physical and mental QOL were improved after treatment with Avonex. In a 15-year follow-up of MS patients, Bermel et al.34 showed that patients continuing to use intramuscular IFN-β-1a had less disability and better QOL compared to those who were not currently using IFN-β. These studies are in line with our findings in principal that DMT have positive effects on the QOL of MS patients. By contrast, Simone et al.19 showed that IFN-β had a negative impact on QOL of MS patients over time, influencing mainly the mental QOL, whereas clinical disability had a minor unfavorable role. There are several explanations for this difference; one could be due to the particular IFN-β treatment that is used, although none of the treatments in our study showed negative impact on QOL. Those authors also mentioned its negative effect was mostly on mental QOL; in our study, two of the treatments had lower but not negligible effect on mental health compared to Betaferon. Also, the limited sample size of the patients in each group (IFN-β-1a: 14 [Avonex] and 16 [Rebif]; IFN-β-1b: 11) could have affected their results, making them different to ours. The results of Zivadinov et al. in MS patients treated with Avonex showed no change in QOL after 1 year of follow up.7 This difference could be explained by the use of tests other than the MSQOL54; it is reasonable to expect that different tests will result in somewhat different outcomes. Also, the group of patients who participated in their study had
a history of previous MS treatments for 6–18 months, which might also have affected the results. We observed an independency between score changes in both QOL composites and the EDSS. We noticed that QOL was enhanced in both the Rebif and Betaferon groups and this was also true for the EDSS; however, in the Avonex group, we observed a setback in disability scores. This might guide us in choosing a more appropriate treatment strategy tailored to the disability status of the patients. DMT have a positive impact on the QOL of MS patients. This effect was observed at a higher level in those taking Betaferon and particularly in mental health. There was no significant difference between these three groups of treatments in terms of improvement in physical health. In conclusion, as the positive effects of IFN-β treatments on the mental and physical dimensions of QOL have been observed using DMT, such medications may provide MS patients with a better QOL. Based on our findings, we recommend that DMT treatment should be initiated as early as possible. In addition, due to the significantly positive impact of Betaferon treatment on mental health, MS patients with more mental issues and fewer physical disabilities may be allocated to consider Betaferon as one of the preferred choices where there is no reason to choose either of the other treatments.
ACKNOWLEDGMENTS The study was supported by a grant from the Vice Chancellor for Research at Mashhad University of Medical Sciences. The authors would like to thank Ms Shahraki for performing the neuropsychological tests and Mr Kyle Boyles for revising the manuscript. None of the authors has anything to disclose.
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Psychiatry and Clinical Neurosciences 2015; 69: 649–657
SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article at the publisher’s web-site:
Quality of life in multiple sclerosis 657
The MSQOL-54 questionnaire6 can be downloaded through the following URL:http://www .nationalmssociety.org/NationalMSSociety/media/ MSNationalFiles/Brochures/MSQOL54_995.pdf Table S1. Demographic data of participants
© 2015 The Authors Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
doi:10.1111/pcn.12308
Regular Article
Therapeutic effect of Avonex, Rebif and Betaferon on quality of life in multiple sclerosis Naghmeh Mokhber, MD,1† Amir Azarpazhooh, PhD,3,4,5† Elias Orouji, MD,2 Bita Khorram, MD,2 Morteza Modares Gharavi, PhD,1 Sorayya Kakhi, MD,2 Hoda Khallaghi, MD2 and Mahmoud Reza Azarpazhooh, MD2* 1 Psychiatry and Behavioral Sciences Research Center, 2Department of Neurology, Ghaem Medical Center, Mashhad University of Medical Sciences, Mashhad, Iran, and 3Department of Biological and Diagnostic Sciences, Faculty of Dentistry, 4Institute of Health Policy, Management and Evaluation, Faculty of Medicine, and 5Toronto Health Economics and Technology Assessment Collaborative, University of Toronto, Toronto, Canada
Aims: The aim of this study was to evaluate the effect of various disease-modifying therapies (DMT) on quality of life in multiple sclerosis (MS). Methods: This was a three-arm parallel study with balanced randomization in which 90 newly diagnosed, definite MS subjects referred to Ghaem Medical Center, Mashhad, Iran were enrolled between 2006 and 2009. Patients were randomly allocated into three DMT groups: Avonex, Rebif and Betaferon. Health-related quality of life was assessed in MS patients at baseline and 12 months after treatment with DMT using the MS Quality of Life-54 questionnaire. Results: Both mental and physical health scores improved within all three treatment groups after 12 months of treatment; however, this increase was only
ULTIPLE SCLEROSIS (MS) is the most common demyelinating disorder of the central nervous system that usually affects young adults.1 The disease is characterized by multifocal, inflammatory, and immune-mediated central nervous system injury,
M
*Correspondence: Mahmoud Reza Azarpazhooh, MD, Department of Neurology, Ghaem Medical Center, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran. Email: [email protected] † These authors contributed equally to the article. Clinical trial registration code: IRCT201404195280N16 (http:// www.irct.ir) Received 17 October 2014; revised 11 March 2015; accepted 18 April 2015.
significant in the mental health composite in the Betaferon group (P = 0.024). Betaferon had the highest mental health score change (14.04) while this change was 7.26 for Avonex (P = 0.031) and 5.08 for Rebif (P = 0.017). A physical health composite score comparison among the three treatment groups revealed no significant results.
Conclusions: With a positive impact of DMT on mental and physical dimensions of QOL in MS patients, initiation of treatment soon after diagnosis is recommended. In MS patients with more mental issues and fewer physical disabilities, Betaferon might be considered as a better choice of treatment. Key words: disease-modifying therapies, multiple sclerosis, quality of life.
which can cause a variety of symptoms and consequently requires comprehensive medical care.2–4 MS, as a long-term illness, can result not only in physical disabilities, but also in substantial mental health problems influencing the quality of life (QOL) of patients, their partners, families, and caregivers.5–7 The health-related QOL, or the capacity to derive satisfaction from meaningful behavior despite disease, is a topic of increasing interest to clinicians caring for MS patients. Hence in patients with MS, apart from complete psychophysical and objective neurologic status, a subjective perception of signs and symptoms, known as QOL, needs to be considered.8 Several studies have clearly shown that MS patients
© 2015 The Authors Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
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have lower QOL scores than healthy controls.5,9 In recent years, there has been an increasing tendency to evaluate the QOL in MS patients as the primary clinical outcome.10,11 Disease-modifying therapies (DMT) have a beneficial effect on the course of MS in terms of reducing the relapse rates and delaying the onset and progression of disabilities.12–17 In spite of limited data on QOL and its correlation with DMT, it is possible that DMT influence the QOL, independent of the physical disabilities.18 As treatment with β-interferon (IFN-β) is a life-long treatment and patients often experience various side-effects, a positive effect on the patient’s QOL is critical.12–14,19 Therefore, this study investigates the effect of DMT (IFN-β-1a [Avonex and Rebif] and IFN-β-1b [Betaferon]) on QOL in a group of MS patients.
distinct commercially available forms of IFN-β: Avonex, Rebif, and Betaferon. Avonex was administered 30 μg once per week via intramuscular injection. Rebif was administered 44 μg three times per week via subcutaneous injection. Betaferon was administered 0.25 mg every other day via subcutaneous injection. Patients (or their caregivers) were trained by the study neurologist (M.R.A.) to self-administer their assigned medication.
METHODS Study design The current study was a single blind, three-arm clinical trial, with balanced randomization to evaluate the effect of IFN-β on QOL of the patients with definite MS. The study was approved by the Ethics Committee of the Mashhad University of Medical Sciences (protocol no. 84394). Written informed consent was obtained from each participant prior to the investigations.
Study population The study began in May 2006, when we began gathering new MS patients, and lasted until June 2009. All new cases of definite MS referred to the Department of Neurology at Ghaem Medical Center, Mashhad, Iran were included in this study. MS was defined according to the revised McDonald criteria, which evaluate frequency of clinical attacks, number of objective lesions and specify additional requirements to make a diagnosis in each case.20 Patients were excluded if they had a history of substance abuse, treatment with any other type of DMT or had any signs of depression using semi-structural psychiatric interviews as well as the Beck Depression Inventory (Fig. 1).
Treatment protocol Patients were randomly assigned using a computergenerated list of random numbers to receive three
Neuropsychological outcome measures The following outcomes were measured at baseline and after 12 months of treatment: 1 QOL was assessed using the Farsi version of the MS Quality of Life (MSQOL)-54 scale,6 which has been previously validated.21 This scale is composed of the Short Form 36-item Health Survey and 18 disease-specific items. This 54-item self-reported questionnaire measures both mental and physical health. The Mental Health (MH) composite consists of five subscales: Health distress, Overall QOL, Emotional well-being, Role limitations due to emotional problems, and Cognitive function. The Physical Health (PH) composite consists of eight subscales: Physical function, Health perceptions, Energy/fatigue, Role limitations due to physical problems, Pain, Sexual function, Social function, and Health distress. MH and PH composite scores could have the value of 0–100 with higher values indicating better QOL. The Health distress scale is the only scale that does not individually load on mental and physical health but has high loadings on both. The internal consistency reliability of the MSQOL-54 test is 0.75–0.96 and the test–retest intraclass correlation coefficient is 0.66–0.96.6 2 The Expanded Disability Status Scale (EDSS) was also performed for all cases to quantify disability in eight Functional Systems. EDSS steps 1.0–4.5 refer to people with MS who are fully ambulatory. EDSS steps 5.0–9.5 are defined by the impairment to ambulation.22
Statistical analyses To investigate the effect of the treatment protocols on QOL, we calculated several sample sizes for each of the MH and PH composites and treatment groups. Then the largest calculated sample size was selected
© 2015 The Authors Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
Psychiatry and Clinical Neurosciences 2015; 69: 649–657
Quality of life in multiple sclerosis 651
Relapsing remitting MS patients assessed for eligibility (n = 90)
Excluded patients (n = 21) Previous treatment with any type of DMT (n = 14) History of substance abuse (n = 3) Signs of depression (n = 4)
Relapsing remitting MS patients who underwent randomization (n = 69)
Allocated for the treatment with Avonex (n = 23)
Allocated for the treatment with Rebif (n = 23)
Allocated for the treatment with Betaferon (n = 23)
Withdrawn/loss to follow up (n = 3) • Refusal (n = 1) • Loss of contact (n = 2) Analyzed for QOL (n = 20)
Withdrawn/loss to follow up (n = 2) • Refusal (n = 2)
Withdrawn/loss to follow up (n = 4) • Refusal (n = 1) • Loss of contact (n = 3) Analyzed for QOL (n = 19)
Analyzed for QOL (n = 21)
Figure 1. Flow diagram of the randomized controlled study. DMT, disease-modifying therapies; MS, multiple sclerosis; QOL, quality of life.
for the study. The minimum sample size of 18 patients per group was calculated using two independent means t-tests. To calculate MH composite score, the final score of each of the five subscales was multiplied by weight for this subscale (respectively, 0.14, 0.18, 0.29, 0.24, and 0.15). These five subtotal values were then added to generate the MH composite score. The same approach was undertaken for the PH composite score, except there were eight subscales, respectively weighted by 0.17, 0.17, 0.12, 0.12, 0.11, 0.08, 0.12, and 0.11.6,19 The percentage of missing data concerning the MSQOL-54 questionnaire was very low, therefore no imputation was performed for the missing data.
Results were compared among and within the three treatment groups to evaluate the impact of intervention medications on patients’ QOL during this 1-year period. Statistical analyses were performed using SPSS 18 (SPSS, Chicago, IL, USA). The Lilliefors (Kolmogorov–Smirnov) test was applied to assure the normal distribution of the data. Parametrical tests, such as paired samples t-tests and analysis of variance with post-hoc analysis using Tukey’s Honestly Significant Difference, were used to assess the statistical significance of the continuous variables, within and among groups, respectively. A value of P ≤ 0.05 was used as a criterion for statistical significance.
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(Table S1). There was no significant difference in age, sex, or education level of participants among the three groups.
RESULTS Demographic data Overall, 90 MS patients participated in this study. A total of 21 patients were excluded due to previous history of using DMT, history of substance abuse, and having signs of depression. The 69 remaining patients were allocated to the three treatment groups (23 patients in each group) and were followed up for a minimum of 12 months. We lost three patients in the Avonex group (one refused to continue, two loss of contact), two patients in the Rebif group (both did not continue the study due to changing their place of residence), and four patients in the Betaferon group (three loss of contact, one refused to continue), leaving us with 60 patients who completed the study (Fig. 1). The mean age of patients was 29.80 ± 7.51 years. There were 21 (35.0%) men and 39 (65.0%) women in the sample
(a)
Health-related QOL In all three treatment groups, Overall QOL scores were increased (Avonex: 58.83 to 65.96; Rebif: 57.46 to 64.27; and Betaferon: 59.42 to 69.15). Scores for both PH and MH composites were increased after 1 year in the whole group of MS patients (PH: 57.69 to 64.44; MH: 59.44 to 68.48). No significant difference was observed in the baseline summary scores of the MSQOL-54, MH and PH among the three groups (P = 0.311). There was a trend towards improvement in the MH and PH scores within each group of treatment after 12 months; however, only the MH composite score in Betaferon-treated patients showed a statistically significant improvement (58.89 to 72.93, P = 0.024) (Fig. 2a).
Summary score (within the groups) *
100
Mean score
80 60 40 20 0 PH
MH
PH
Avonex
MH
PH
Rebif
MH Betaferon
(b)
Score change (Δ) *
Summary score change 20 18 16 14 12 10 8 6 4 2 0 PH
(P = 0.031)* (P = 0.017) *
MH
Figure 2. (a) Comparison of summary score at ( ) baseline and ( ) after 12 months within each treatment group for the physical health (PH) and mental health (MH) components. (b) Comparison of summary score change between the ( ) Avonex, ( ) Rebif and ( ) Betaferon groups for the PH and MH components.
© 2015 The Authors Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
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Quality of life in multiple sclerosis 653
Table 1. MSQOL-54 and EDSS values at baseline and after 12 months of treatment in the different treatment groups
Baseline
12 months
Pvalue
Baseline
12 months
Pvalue
Baseline
12 months
Palue
P-value (changes in three groups)
56.82 ± 22.99 44.82 ± 28.59 55.12 ± 13.35 45.25 ± 17.17 61.83 ± 25.92
63.83 ± 23.29 48.35 ± 18.29 75.94 ± 11.65 34.83 ± 20.08 72.08 ± 28.67
NS NS 0.046 NS NS
56.31 ± 19.12 40.71 ± 17.59 52.53 ± 16.12 47.50 ± 16.67 39.92 ± 17.58
64.14 ± 25.84 48.41 ± 20.29 65.41 ± 18.18 67.67 ± 15.58 42.42 ± 23.92
NS NS NS 0.036 NS
59.96 ± 27.45 41.82 ± 27.76 66.18 ± 18.00 66.75 ± 25.25 40.00 ± 18.33
65.37 ± 28.65 49.76 ± 31.18 62.00 ± 23.65 78.58 ± 23.00 43.50 ± 19.75
NS NS NS NS NS
NS NS 0.009 0.031 0.043
76.09 ± 29.00 53.00 ± 28.50 60.25 ± 26.17 64.91 ± 18.91 60.84 ± 18.13 64.93 ± 20.79 59.00 ± 10.83 64.45 ± 19.48 46.71 ± 18.08
87.64 ± 38.64 58.25 ± 32.35 65.83 ± 27.17 69.73 ± 20.55 68.1 ± 20.72 69.71 ± 14.57 65.44 ± 14.11 63.72 ± 21.17 59.33 ± 22.04
NS NS NS NS NS NS NS NS NS
86.45 ± 22.55 72.88 ± 28.13 65.50 ± 19.83 61.55 ± 19.73 58.61 ± 19.82 61.50 ± 20.29 50.61 ± 11.39 58.86 ± 18.28 49.67 ± 17.75
84.73 ± 35.18 69.38 ± 39.25 67.17 ± 29.50 78.64 ± 36.45 64.41 ± 23.65 78.64 ± 28.79 64.06 ± 18.94 66.52 ± 23.10 43.29 ± 21.42
NS NS NS NS NS NS NS NS NS
91.27 ± 59.45 62.63 ± 23.38 54.92 ± 24.50 65.00 ± 28.09 58.89 ± 24.31 67.14 ± 29.64 39.17 ± 19.72 68.55 ± 23.24 53.00 ± 23.04
86.91 ± 50.36 69.13 ± 30.38 64.25 ± 27.83 81.09 ± 26.27 72.93 ± 28.12 81.79 ± 28.07 75.33 ± 37.28 78.31 ± 24.48 60.17 ± 20.79
NS NS NS NS 0.024 NS 0.021 NS NS
0.038 NS NS NS 0.017 NS 0.021 0.034 0.019
74.87 ± 20.27 1.5 ± 1.0
92.27 ± 31.40 1.5 ± 0.6
NS 0.548
79.33 ± 35.80 2.3 ± 1.5
81.27 ± 29.13 1.3 ± 0.9
NS 0.001
65.60 ± 28.93 2.1 ± 1.0
71.80 ± 35.93 1.5 ± 1.0
NS 0.028
0.026 0.003
Avonex
MSQOL-54 MSQL-PH Physical function Health perceptions Energy/fatigue Role limitations – physical Pain Sexual function Social function Health distress MSQOL-MH Health distress Overall quality of life Emotional well-being Role limitations – emotional Cognitive function EDSS
Rebif
Betaferon
Bold font indicates summary scores and significant P-values. EDSS, Expanded Disability Status Scale; MH, mental health; MSQOL, Multiple Sclerosis Quality of Life scale; NS, not significant; PH, physical health.
Within each group, there were specific subscales that changed significantly after 12 months. These included the Health perception subscale in the Avonex group (change = 20.82, P = 0.046), the Energy/fatigue subscale in the Rebif group (change = 20.17, P = 0.036) and the Overall QOL as a subscale of MH in the Betaferon group (change = 36.17, P = 0.021). Among the study groups, Avonex had the best effects on MS patients in terms of the Health perception (P = 0.009), Role limitations – physical (P = 0.043), Pain (P = 0.038), Role limitation – emotional (P = 0.019) and Cognitive function subscales (P = 0.026). Rebif had the best effects on the Energy/fatigue subscale (P = 0.031). Betaferon improved the Overall QOL (P = 0.21) and Emotional well-being (P = 0.034) subscales better than the other two treatments (Table 1, Fig. 3). Figure 2b presents the inter-group comparisons. No significant difference in PH composite score was found among the three groups. Yet a significant change on the MH composite score was noted in the Betaferon group (14.04) as compared to the Avonex (7.26, P = 0.031) and Rebif (5.08, P = 0.017) groups.
Disability There was no difference in the EDSS baseline values among the three treatment groups (P = 0.37). The
baseline range of EDSS was 0–5.5 and this range was 0–4.0 after 12 months of treatment. Within each group, participants who received Rebif (P = 0.001) and Betaferon (P = 0.028) experienced an improvement in their disability; however, those who received Avonex did not (P = 0.548). Inter-group comparison between the three groups indicated Rebif to have the best effect on the improvement of disability in MS, and Avonex to have the least impact (P = 0.003) (Table 1).
DISCUSSION QOL is an important aspect of health in patients with MS. Previous studies have shown that QOL measurements are constantly lower in patients with MS.9,23–25 The assessment of QOL is being increasingly recognized as a method to analyze the efficacy of different treatment modalities.5,7–9,18,26–30 In particular, it has been shown that DMT can improve some aspects of patients’ QOL.18,26–30 To date, there is no study addressing the comparison between different treatment options. Hence, we designed this single blind clinical trial to investigate the effect of IFN-β-1a (Avonex and Rebif) and IFN-β-1b (Betaferon) on QOL in a group of patients with definite MS. Due to the unavailability of glatiramer acetate (Copaxone) on a large scale in Iran, we were not able to include it
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MSQOL-54 subscale score change
10
*
8
Score change (Δ)
6 *
* 4 *
* *
* *
2
0
Physical healt h
Cognitive function
Role limitations – emotional
Emotional well-being
Overall quality of life
Health distress
Health distress
Social function
Sexual function
Pain
Role limitations - physical
Energy/fatigue
Health perceptions
−4
Physical function
−2
M ent al healt h
Figure 3. Comparison of subscale score change between the ( ) Avonex, ( ) Rebif and ( ) Betaferon groups. MSQOL-54, Multiple Sclerosis Quality of Life-54 scale.
in our study. Furthermore, due to the need for administration of comprehensive tests to assess sideeffects of these treatments, including depression, which is believed to be worsened, these side-effects were not investigated here. We used the MSQOL-54 as a self-administered, multidimensional healthrelated QOL measure, which combines both generic and MS-specific items into a single instrument. It is the most frequently used specifically MS questionnaire. This questionnaire has a high test–retest reliability and internal consistency with evidence supporting its content and construct validity.6 Our study population constituted newly diagnosed MS patients who had not taken any previous treatment for MS. Such homogeneity eliminates the bias
of the late effects of other previous treatments on measuring QOL; however, we were limited with respect to the number of patients in each group. Our results showed a significant improvement in the MH composite of the MSQOL-54 after 12 months of treatment with Betaferon compared to the Avonex and Rebif groups. Moreover, all of the subscales of MH in the Betaferon group showed an improving trend, while for the other two groups, we noticed decreasing values in at least one of the subscales. However, it should be noted that each individual subscale might or might not be in line with the composite improvement. Unlike mental health, physical health showed the lowest improvement in the Betaferon group com-
© 2015 The Authors Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
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Quality of life in multiple sclerosis 655
pared to the Avonex and Rebif groups and the best improvement was seen in the Avonex group. In general, no obvious difference was observed in terms of the PH or MH composites in the Avonex and Rebif groups. However, the impact of these two treatments was different to that of Betaferon, which acts relatively better in MH scales. IFN-β could prevent MS attacks, improve the physical status of the patients and consequently lead to the improvement of QOL. It is also possible that these treatments can change the course of the disease by improving cognitive status and hence, directly affecting the patients’ QOL.31 Furthermore, the impact of IFN on the immune system may also lead to overall well-being in patients. In a large group of untreated MS patients, Putzki et al.32 found that treatment initiation with intramuscular IFN-β-1a attenuates MS disease activity and improves QOL. Similarly, in a 2-year follow-up study, Jongen et al.33 found that physical and mental QOL were improved after treatment with Avonex. In a 15-year follow-up of MS patients, Bermel et al.34 showed that patients continuing to use intramuscular IFN-β-1a had less disability and better QOL compared to those who were not currently using IFN-β. These studies are in line with our findings in principal that DMT have positive effects on the QOL of MS patients. By contrast, Simone et al.19 showed that IFN-β had a negative impact on QOL of MS patients over time, influencing mainly the mental QOL, whereas clinical disability had a minor unfavorable role. There are several explanations for this difference; one could be due to the particular IFN-β treatment that is used, although none of the treatments in our study showed negative impact on QOL. Those authors also mentioned its negative effect was mostly on mental QOL; in our study, two of the treatments had lower but not negligible effect on mental health compared to Betaferon. Also, the limited sample size of the patients in each group (IFN-β-1a: 14 [Avonex] and 16 [Rebif]; IFN-β-1b: 11) could have affected their results, making them different to ours. The results of Zivadinov et al. in MS patients treated with Avonex showed no change in QOL after 1 year of follow up.7 This difference could be explained by the use of tests other than the MSQOL54; it is reasonable to expect that different tests will result in somewhat different outcomes. Also, the group of patients who participated in their study had
a history of previous MS treatments for 6–18 months, which might also have affected the results. We observed an independency between score changes in both QOL composites and the EDSS. We noticed that QOL was enhanced in both the Rebif and Betaferon groups and this was also true for the EDSS; however, in the Avonex group, we observed a setback in disability scores. This might guide us in choosing a more appropriate treatment strategy tailored to the disability status of the patients. DMT have a positive impact on the QOL of MS patients. This effect was observed at a higher level in those taking Betaferon and particularly in mental health. There was no significant difference between these three groups of treatments in terms of improvement in physical health. In conclusion, as the positive effects of IFN-β treatments on the mental and physical dimensions of QOL have been observed using DMT, such medications may provide MS patients with a better QOL. Based on our findings, we recommend that DMT treatment should be initiated as early as possible. In addition, due to the significantly positive impact of Betaferon treatment on mental health, MS patients with more mental issues and fewer physical disabilities may be allocated to consider Betaferon as one of the preferred choices where there is no reason to choose either of the other treatments.
ACKNOWLEDGMENTS The study was supported by a grant from the Vice Chancellor for Research at Mashhad University of Medical Sciences. The authors would like to thank Ms Shahraki for performing the neuropsychological tests and Mr Kyle Boyles for revising the manuscript. None of the authors has anything to disclose.
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© 2015 The Authors Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
Psychiatry and Clinical Neurosciences 2015; 69: 649–657
SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article at the publisher’s web-site:
Quality of life in multiple sclerosis 657
The MSQOL-54 questionnaire6 can be downloaded through the following URL:http://www .nationalmssociety.org/NationalMSSociety/media/ MSNationalFiles/Brochures/MSQOL54_995.pdf Table S1. Demographic data of participants
© 2015 The Authors Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
